The dopamine transporter is a principal target of cocaine in brain. Cocaine congeners that bind to the dopamine transporter are useful as imaging agents and have been proposed as cocaine substitutes. Detailed structure-activity studies with cocaine isomers and phenyltropane analogs of cocaine such as WIN 35,428, have generated principles regarding the binding domain for cocaine/cocaine congeners on the dopamine transporter. High affinity binding is thought to be conferred by 2 and 3 substituents on the tropane ring and the R isomeric form. In order to develop compounds with improved binding properties and to expand the structure-activity framework, a novel series of benztropine analogs were prepared. Benztropine was selected because, in contrast to cocaine and WIN 45,428, it has no substituent on the 2 -position and its 3-substituent is in the 3a position. In further contrast, although benztropine has moderate affinity for the dopamine transporter, it has relatively high selectivity for the dopamine over the serotonin transporter. In order to determine whether a combination of these structural features could result in compounds retaining the favorable properties of both classes of drugs, a novel series of benztropine derivatives, containing a carbomethoxy group in various positions and substituents on the aromatic rings were synthesized and evaluated. In cynomolgus monkey striatum, in marked contrast to R-cocaine or to R-WIN 35,428, S-difluoropineTM (2 -carbomethoxy-3a-methoxydifluorophenyltropane) was the active form. It bound the dopamine transporter with high affinity (IC50 10.9nM), stereoselectivity (200-fold, S- over the R-form) and DA/5HT selectivity (324-fold). We have now extended this series to evaluate the effects of substituents on the nitrogen and the diarylmethoxy group, the series of 2-carbomethoxy-3-(diarylmethoxy)-1`2H,5`H-tropane(2-carbomethoxybenztropine) analogs. The binding data for these compounds indicates that while the 4,4'-difluoro compound is potent and selective for the dopamine transporter, introduction of larger groups such as 4,4'-dichloro, 4,4'-dibromo, 4,4'-diiodo, or 4,4'-dimethyl on the 3-diphenylmethoxy moiety reduces this potency. However, although introduction of only one group (e.g., 4-chloro, 4-bromo, 4-iodo, or 4-methyl) leads to a similar reduction of binding affinity, these monosubstituted 2-carbomethoxybenztropines are significantly more potent than the related disubstituted compounds. Finally, from the data for the N-substituted 2-carbomethoxybenztropine analogs, it is evident that steric bulk can be tolerated at the nitrogen site. A comparison of structure-activity relationship data for the tropanes, GBR analogs, and these benztropines indicates that the 2-carbomethoxy-benztropine analogs may be more like the GBR analogs in their mode of binding to the dopamine transporter than like the tropanes. This conclusion supports the notion that the binding domain for (-)-cocaine [and the (1R)-tropanes] may differ from that of the 2-carbomethoxybenztropine analogs. These studies also highlight the high capacity